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Aip1p Dynamics Are Altered by the R256H Mutation in Actin
Published on: July 30, 2014
A recurrent ACTA1 amino acid change in mosaic form causes milder asymmetric myopathy
Vilma-Lotta Lehtokari1, Lydia Sagath1, Mark Davis2
1Folkhälsan Research Center, 00290 Helsinki, Finland; Department of Medical and Clinical Genetics, Medicum, 00014 University of Helsinki, Finland.
Abstract:
We describe three patients with asymmetric congenital myopathy without definite nemaline bodies and one patient with severe nemaline myopathy. In all four patients, the phenotype had been caused by pathogenic missense variants in ACTA1 leading to the same amino acid change, p.(Gly247Arg). The three patients with milder myopathy were mosaic for their variants. In contrast, in the severely affected patient, the missense variant was present in a de novo, constitutional form. The grade of mosaicism in the three mosaic patients ranged between 20 % and 40 %. We speculate that the milder clinical and histological manifestations of the same ACTA1 variant in the patients with mosaicism reflect the lower abundance of mutant actin in their muscle tissue. Similarly, the asymmetry of body growth and muscle weakness may be a consequence of the affected cells being unevenly distributed. The partial improvement in muscle strength with age in patients with mosaicism might be due to an increased proportion over time of nuclei carrying and expressing two normal alleles.
Insights
Mosaic ACTA1 variants cause milder congenital myopathy, while de novo variants lead to severe forms. Mosaicism may explain varying disease severity and asymmetry in actin myopathy patients.
Area of Science:
- Genetics
- Neurology
- Pathology
Background:
- Congenital myopathies are a group of inherited muscle disorders.
- ACTA1 gene variants are a known cause of nemaline myopathy.
- The role of mosaicism in ACTA1-related myopathies requires further investigation.
Purpose of the Study:
- To investigate the clinical and genetic spectrum of ACTA1-related congenital myopathies.
- To explore the impact of mosaicism versus de novo mutations on disease presentation.
- To understand the genotype-phenotype correlation in ACTA1 myopathy.
Main Methods:
- Clinical case descriptions of four patients with congenital myopathy.
- Genetic analysis to identify ACTA1 variants.
- Assessment of variant type (mosaic vs. de novo) and level of mosaicism.
Main Results:
- Identified pathogenic ACTA1 missense variants (p.Gly247Arg) in all four patients.
- Three patients presented with asymmetric congenital myopathy and mosaic variants (20-40% mosaicism).
- One patient had severe nemaline myopathy with a de novo, constitutional variant.
Conclusions:
- The same ACTA1 variant can cause a spectrum of congenital myopathies, from mild asymmetric to severe nemaline myopathy.
- Mosaicism for ACTA1 variants is associated with milder phenotypes, potentially due to lower mutant actin levels.
- Asymmetry and variable improvement may relate to mosaic distribution and allele proportions.
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